AB0081 BIODISTRIBUTION OF NIPOCALIMAB (ANTI-HUMAN FcRn ANTIBODY) IN huFcRn TRANSGENIC MICE
Authors: A. Vermeulen, J. H. Leu, S. Sipsey, S. Lee, L. Ling
Journal: Annals of the Rheumatic Diseases (2022)

Background Nipocalimab (JNJ-80202135, M281) is a fully human IgG1 monoclonal antibody (mAb) designed to bind to the human FcRn receptor with high affinity at both neutral and acidic pH, and is currently in investigational clinical trials. The primary role of FcRn is to extend the half-life of IgG due to its ability to bind, salvage, and recycle IgG in the circulation. Nipocalimab specifically targets the FcRn IgG binding site, thereby interfering with the binding of native IgG, reducing IgG recycling and accelerating IgG clearance (1). Objectives To determine the biodistribution of nipocalimab compared to an isotype control IgG in huFcRn transgenic (Tg32) mice. This type of study is well suited to non-invasively determine the blood PK of labeled antibodies, as well as the kinetic biodistribution into various organ systems. Methods Four formulations were prepared for dosing: nipocalimab-VT680XL (N027a), nipocalimab-VT680XL plus 2x unlabeled nipocalimab (N027b), isotype control IgG-VT680XL and control vehicle. The biodistribution assessment experiments were performed in Tg32 mice (n=3/group, strain: B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ). A time series of in vivo fluorescence-mediated tomography (FMT) imaging sessions of body and brain was collected to follow the biodistribution of antibodies (Abs) after single IV administration. In vivo , whole body fluorescence was assessed immediately after administration of each formulation, and at 1, 5, 24, 48, 72, 96 and 144 hrs post administration. Mice were sacrificed after the final in vivo imaging timepoint, followed by resection of tissues and ex vivo imaging. The in vivo tissues were also assessed ex vivo at the terminal time point by epifluorescence. Ex vivo epifluorescence measurements were obtained for gall bladder, muscle, spleen, pancreas, white blood cells, lymph nodes, and intestines, which were flushed prior to imaging to remove fecal material. Results Biodistribution of nipocalimab and control IgG1 mAb were similarly observed to exhibit 2-compartment blood pharmacokinetics, dominant liver accumulation with minimal kidney and bladder signal and a prolonged terminal half-life in circulation (70-90 h). Nipocalimab showed only subtle differences compared to IgG1 control antibody, attributed to specific binding to target antigen. Early tissue accumulation/binding was seen between 1 and 5 hrs post-injection, which yielded an apparent, modest increase in blood clearance and a slightly lower AUC as compared to control IgG. The bulk of increased tissue binding could be attributed to liver retention, with trends for lower accumulation/binding in other tissues, such as pancreas, lung, and muscle. Addition of 2-fold excess of unlabeled nipocalimab to the labeled nipocalimab yielded some small trends of changes in biodistribution of the labeled material. Conclusion Whole body biodistribution and blood pharmacokinetics of nipocalimab were similar to that observed for the isotype control IgG1 antibody. Nipocalimab exhibited a subtle trend towards higher liver distribution within the first 5 hours after dosing and a more rapid distribution phase compared to the control antibody. This is possibly related to its FcRn targeting and its shorter anticipated half-life compared to isotype control IgG or other human IgG mAbs. Overall results for both nipocalimab and control IgG were typical for IgG mAbs. References [1]Ling L. et al. M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study. Clin. Pharm. Ther. 2019;105(4):1031-1039. Acknowledgements We would like to acknowledge Brigit Schultes and Sucharita Roy (Momenta Pharmaceuticals Inc.) and Jeff Peterson (Perkin Elmer) for their help with the execution of the study. Disclosure of Interests An Vermeulen Shareholder of: J&amp;J participating in employee stock programs and full-time employee of Janssen Pharmaceuticals, a J&amp;J company, Jocelyn H Leu Shareholder of: J&amp;J participating in employee stock programs and full-time employee of Janssen Pharmaceuticals, a J&amp;J company, Sandy Sipsey Shareholder of: J&amp;J participating in employee stock programs and full-time employee of Janssen Pharmaceuticals, a J&amp;J company, Stan Lee Shareholder of: J&amp;J participating in employee stock programs and full-time employee of Janssen Pharmaceuticals, a J&amp;J company, Leona Ling Shareholder of: J&amp;J participating in employee stock programs and full-time employee of Janssen Pharmaceuticals, a J&amp;J company